Invariant natural killer T (iNKT) cells are innate lymphocytes whose functions are regulated by CD1d- restricted self and foreign glycolipid antigens. Humans develop a homologous T cell subset and, hence, much of what is learnt in mice can be extended to people as well. Emerging evidence indicates that iNKT cell deficiency in mice delays bacterial clearance and immunity to them. Nonetheless, there is a major gap in our understanding of the precise role(s) iNKT cells play in conferring immunity to pathogens that cause human diseases in natural settings. To narrow this gap is highly significant because knowledge-based therapies, vaccine design and vaccination strategies against infectious diseases require an in-depth understanding of host responses to the inciting pathogen. Thus, the long-term goal of this project is to delineate the mechanism(s) by which iNKT cells regulate immunity to infectious diseases. Toward this goal, we have made significant new advances on the role of mouse iNKT cells in host response to Francisella tularensis (Ft). Ft subspp. tularensis, a Category A agent and potential bioweapon, causes lethal tularemia in people. Using a mouse model for this disease, we found that within a day, Ft subspp. novicida and the live vaccine strain (LVS) infection activated mouse splenic and hepatic iNKT cells to produce interferon-?, a key mediator of Ft clearance in both mice and humans. Further, iNKT cell deficiency increased splenic and hepatic Ft novicida load. Significantly, Ft inoculated wild type, but not iNKT cell deficient mice rapidly produced proinflammatory cytokines and chemokines, became morbid and died within a week. Guided by these exciting new preliminary data, we hypothesize that iNKT cell activation is critical for the control of Ft infection but the overzealous iNKT cell function leads to morbidity and mortality and fine-tuning these responses is essential for the control of microbial infections. To test this central hypothesis, we will: (1) elucidate the mechanism(s) by which iNKT cells regulate immunity to Ft and/or precipitate infection-induced disease;(2) determine the chemical nature of the Ft-derived antigen(s) that activates iNKT cells;and (3) develop ways to inhibit, deviate or deplete iNKT cells as a means to temper or prevent Ft infection-induced disease. New insights emerging from this study will significantly impact how we concoct iNKT cell-based therapies and vaccines and design vaccination strategies to pathogens that plague human kind. PUBLIC HEALTH RELEVANCE: Francisella tularensis infections, which causes severe acute lethal tularemia, is considered a Category A pathogen and a serious bio-weapon because of the ease with which it can be grown in large quantities and made air-borne. The research proposed in this application will elucidate the mechanism(s) by which a subset of immune defense cells called natural killer T cells cause the pathogenesis of tularemia. The emerging new insight will then define ways to design novel vaccines to prevent the disease and to develop novel therapies to treat non-vaccinated individuals infected with Francisella tularensis.